The present invention relates generally to diastereomeric mono- and dihydroxylated diamino cyclohexane compounds and the methods for preparing them in a stereocontrolled manner. The invention also relates to the use of such compounds as synthons in the preparation of platinum complexes for such pharmaceutical uses as antitumor agents.
Vicinal, 1,3-, and 1,4-relationships of O and N functions in pharmacologically active compounds are of particular interest in drug design. In particular, appropriately functionalized aminocyclitols of the cyclohexane diol diamine type serve as synthons for cyclic and acyclic compounds. The synthons are useful for mechanism-based stereostructure-activity investigations in numerous biological systems. A synthon is a structural unit within a molecule which is formed and/or assembled by conceivable synthetic operations. These operations refer not to laboratory manipulations, but to structural transformations in the molecular sense. A synthon is an idealized fragment produced by bond disconnection during a retrosynthetic analysis. Synthons also serve as the focal point for the facile elaboration of compounds with a diversity of pharmacological activity. Thus, a single generic synthon provides avenues for entry into a range of biological areas. A number of synthons have been produced from such compounds as carbohydrates and amino acids which permit the implementation of this conceptual strategy in the organic synthesis of cyclic and acyclic compounds.
To be useful for biological investigations, the synthon must provide isomeric compounds since many pharmacological systems display enantio- and diastereo- meric preferences. Incorporation into a pharmacological system of functional substituents which are suitable for conversion into various targets of biological interest is an important factor in selecting a synthon. The functional substituents must be able to impose a high degree of either enantio- or diastereo-meric control during key reactions.
To be most useful, the synthon must be able to strike a positional balance in a particular synthetic scheme, be sufficiently complex in structure, and be available in sufficient quantity so that divergent syntheses may be completed. In addition, synthons useful in medicinal chemistry must be convertible to several biologically different targets, have a wide isomeric pool, and be readily available and facilitate inexpensive preparation.
In particular, cyclohexane diol-diamine types of aminocyclitols serve as synthons and are found in such substances as streptamine, epistreptamine, 2-deoxystreptamine, 2,5- and 2,6-dideoxystreptamine, actinamine and fortamine. While these substances occupy an important place in antimicrobial chemotherapy, the cyclohexane diol-diamines, as a group, have received relatively little attention. Although there are eleven possible regioisomeric cyclohexane diol-diamines 1-11, as shown below, previous synthetic efforts have centered mainly on regioisomers 5-10. Selected diastereomers of the 5-10 compounds have been employed as mutasynthons for the preparation of new antibiotics having altered sensitivity to plasmid- and nonplasmid- mediated bacterial resistance. Also, one stereoisomer, reported in Kuglov et al., Vesti. Akad. Navak BSSR, Ser. Khing Navuk, 1981, 5, 66-71, of compound 7 possesses antihypertensive activity. ##STR1##
Only certain regioisomers of cyclohexane diol-diamines have been synthesized and biologically investigated for use as synthons. In particular, only the synthesis of derivatives of compound 1 has been performed, as reported in Kresze, G. and Melzer, H., Justus Liebige Ann. Chemie, 1874 (1981).
While this cyclohexane diol-diamine nucleus is useful as a synthon, the synthon capabilities embodied in 4 have not been previously investigated, nor has there been any investigation into the use of synthons such as the cyclohexane diol diamine nucleus as a synthon for the synthesis of analogs of the organo platinum antitumor agent, cisdiammin dichloro platinum II (cisplatin). Cisplatin is used for patients with a variety of terminal malignancies. However, the clinical utility of the antitumor agent cisplatin is limited by severe nephrotoxicity where damage is directly correlated with the dosage and ranges from tubular swelling to total necrosis. Other side-effects include ototoxicity leading to high frequency hearing loss and mental confusion. Therefore, while cisplatin has shown to be beneficial in a broad spectrum of antitumor activity, there is a need for continued research for improved congeners of cisplatin with reduced nephrotoxic and emetic effects.
One successor to cisplatin is the dichloro trans-1,2-diaminocyclohexane Pt(II) complex 13a which displays high activity against a broader range of tumors than cisplatin, and a lack of cross resistance without significant nephrotoxicity. However, this compound 13a has a low therapeutic index which imposes dosage limits on the course of therapy. Also, since the 13a compound lacks sufficient aqueous solubility it is very difficult to make pharmaceutical formulations for intravenous administration. ##STR2##
In an effort to overcome these problems, modifications to 12 focus primarily on the chloride leaving groups such as substitution of either malonate, 13b or sulfate, 13c for the chloride ions. The sulfato analog 13c is very water soluble and highly reactive. However, 13c retains a high degree of toxic potential and suffers from stability problems in aqueous formulations as a result of this chemical lability. Bidentate carboxylate ligands, such as malonate 13b are at the other end of the reactivity spectrum. Much higher doses of 13b are needed than would otherwise be employed and such higher doses lead to neurological and otological toxicities as well as significant myelosuppression.
In light of the importance of developing synthons useful in biological investigations, it can readily be appreciated that a need exists for the development of novel synthons which provide isomeric compounds capable of being converted to several biologically active pharmaceutical compounds. There is a need for synthons which are capable of imposing a high degree of enantio and/or diastereomeric control during various key reactions in the synthesis of the pharmaceutical compounds. There is a further need for the development of synthons useful in medicinal chemistry which are readily available and which facilitate inexpensive preparation of the desired pharmaceutical compounds.
It can also readily be appreciated that a need exists for the development of new organoplatinum chemotherapeutic compounds less toxic than the known cisplatin compound which can be readily prepared from synthons capable of imposing diastereomeric control during the synthesis of such chemotherapeutic compounds. There is a further need for organoplatinum compounds which are more active than cisplatin and have a greater spectrum of anti-tumor efficacy than cisplatin. There is another need for organoplatinum compounds which show a wide range of activity and which do not lead to additive toxicity when used alone or in combination with other therapeutic agents.
There is still another need for attractive synthetic routes for the preparation of such synthons and the novel organoplatinum compounds prepared therefrom.